Mass Spectrometers (MS), have been used to solve an array of analytical problems involving solid, gas and liquid phase samples with both on-line and off-line techniques. On-line Gas Chromatography (GC), Liquid Chromatography (LC), Capillary Electrophoresis (CE) gas and other solution sample separation systems have been interfaced on-line to mass spectrometers configured with a variety of ion source types. Some ion source types operate at or near atmospheric pressure and other ion source types produce ions in vacuum. Mass spectrometers operate in vacuum with different mass analyzer types requiring different vacuum background pressure for optimal performance. The present invention comprises a configuration of one or more multipole ion guides configured in a mass spectrometer. Although the invention can be applied to multipole ion guides comprising any number of poles, the description of the invention given below will present quadrupole or four pole ion guide assemblies. Higher mass to charge separation resolution can be achieved with quadrupole ion guides when compared with the performance of ion guides configured with more that four poles. Quadrupole ion guides have been configured as the primary elements in single and triple quadrupole mass analyzers or as part of hybrid mass spectrometers that include Time-Of-Flight, Magnetic Sector, Fourier Transform and even three dimensional quadrupole ion trap mass analyzers. Typically, quadrupole ion guides operated in mass to charge selection mode, are run in background vacuum pressures that avoid or minimize ion to neutral background gas collisions. A wider range of background pressures have been used when operating quadrupoles in RF only ion transmission mode. For some applications, pressure in a quadrupole ion guide operating in RF only ion transmission mode is maintained sufficiently high to promote collisional damping of ion kinetic energy or Collisional Induced Dissociation (CID) fragmentation of ions traversing the ion guide length.
Commercially available, quadrupole mass analyzers with electron multiplier or photomultiplier detectors are operated in analytical mass to charge selection mode at background pressures typically below 2×10−4 tort range. There are examples of multipole ion guides operated at elevated background pressures I vacuum with some degree of ion mass to charge separation. U.S. Pat. Nos. 5,401,962 and 5,613,294 describe a small quadrupole array with an electron ionization (EI) ion source and a faraday cup detector which can be operated as a low mass to charge range gas analyzer at background pressures up to 1×10−2 torr. Performance of this short quadrupole array begins to decrease when the background pressure increases to the point where the mean free path of an ion is shorter than the quadrupole rod length. U.S. Pat. No. 5,179,278 describes a quadrupole ion guide configured to transmit ions from an Atmospheric Pressure Ionization (API) source into a three dimensional quadrupole ion trap. The quadrupole ion guide described in U.S. Pat. No. 5,179,278 can be operated as a trap to hold ions before releasing the trapped ions into the three dimensional quadrupole ion trap. During ion trapping, the potentials applied to the rods or poles of this quadrupole ion guide can be set to limit the range of ion mass to charge values released to the ion trap. The quadrupole ion guide can also be operated with resonant frequency excitation collisional induced dissociation fragmentation of trapped ions prior to introducing the trapped fragment ions into the three dimensional ion trap. After the quadrupole ion guide has released its trapped ions to the three dimensional ion trap, it is refilled during the three dimensional ion trap mass analysis time period. A quadrupole ion guide that extends continuously through multiple vacuum pumping stages is described in pending U.S. patent application Ser. No. 08/694,542. A portion of the quadrupole ion guide length is positioned in a vacuum region that pressures greater than one millitorr insuring ion and neutral gas background collisions. Pending U.S. patent application Ser. No. 08/694,542 describes a hybrid mass spectrometer wherein the multiple vacuum stage multipole ion guide is configured with a Time-Of-Flight (TOF) mass analyzer. As described, the quadrupole ion guide is operated in combinations of ion transmission, ion trapping, mass to charge selection and CID fragmentation modes coupled with Time-Of-Flight mass to charge analysis. The hybrid quadrupole Time-Of-Flight apparatus and method described provides a range of MS/MSn mass analysis functions. In an improvement over the prior art, one embodiment of the present invention comprises multiple quadrupole ion guides configured and operated in a higher pressure vacuum region of a hybrid TOF mass analyzer improving the mass analyzer MS/MSn performance and analytical capability.
Multipole ion guides operated in RF only mode at elevated pressures have been used as an effective means to achieve damping of ion kinetic energy during ion transmission from Atmospheric Pressure Sources to mass analyzers. A quadrupole ion guide, operated in RF only mode in background pressures greater than 10−4 torr, configured to transport ions from an API source to a quadrupole mass analyzer is described in U.S. Pat. No. 4,963,736. Ion collisions with the neutral background gas serve to damp the ion kinetic energy during ion transmission through the ion guide. This potentially can reduce the primary ion beam energy spread and improve ion transmission efficiency. Multipole ion guides operated in elevated background pressures have been used extensively as collision cells for the CID fragmentation of ions in triple quadrupoles and hybrid magnetic sector and TOF mass analyzers. Ion guides configured and operated as collision cells are run in RF only mode with a variable DC offset potential applied to all rods. U.S. Pat. No. 5,847,386 describes the configuration a multipole ion guide assembly configured to create an electric field along the ion guide axis to move ions axially through a collision cell or to promote CID fragmentation within a collision cell by oscillating ions axially back and forth within the individual ion guide assembly length. As described, the ion guide assembly with an axial field is operated in RF only mode with a common RF applied to all poles of the quadrupole ion guide assembly. Multipole ion guide collision cells that have been incorporated in commercially available mass analyzers and that have been described in the literature are configured as individual ion guide assemblies isolated in a vacuum pumping stage or contained in a surrounding enclosure. The ion guide surrounding enclosure, generally located in a lower pressure vacuum region, is configured to minimize the higher pressure collision cell background pressure from entering the surrounding lower vacuum pressure chamber. Commercially available triple quadrupoles, shown as prior art in FIG. 20 generally are configured with three multipole ion guides in one vacuum pumping stage. The elevated pressure within the collision cell is maintained by leaking collision gas into the enclosure surrounding the collision cell multipole ion guide. Gas leaks out of the collision cell through the enclosure entrance and exit apertures configured along the triple quadrupole centerline. One aspect of the present invention is the configuration of multiple quadrupole ion guides positioned in a common region of higher vacuum pressure higher pressure run in ion mass to charge selection and CID fragmentation operating modes. A further aspect of the invention is the configuration of multiple quadrupole ion guides in a vacuum region of elevated pressure wherein each quadrupole can be operated in mass to charge selection and/or ion fragmentation modes to achieve MS/MSn mass analysis functions.
Conventional triple quadrupole mass analyzers interfaced to API sources must be configured with sufficient vacuum pumping speed in the mass analyzer vacuum stage region to maintain a vacuum level that prevents ion collisions with the background gas. The low pressure vacuum must be maintained while gas leaks into the chamber from the collision cell and the ion source. Vacuum pressure in the collision cell enclosure is generally maintained at 5 to 8 millitorr and the analyzer vacuum stage is maintained in the low 10−5 to 10−6 tort range. FIG. 20 is a diagram of the multipole ion guide configuration of a typical triple quadrupole mass analyzer 150 interfaced to an Atmospheric Pressure Ion source. Individual multipole ion guide assemblies 158, 154, 155 and 156 are configured along the same centerline axis in a three stage vacuum pumping system. Orifice plate 164 provides a leak from atmospheric pressure region 160 into first vacuum stage 151. Ions produced in atmospheric pressure region 160 are transferred into vacuum through a supersonic free jet expansion formed on the vacuum side of orifice 169. A portion of the ions introduced into vacuum continue through the orifice in skimmer, multipole ion guide 158, the orifice in electrode 161, multipole ion guide 154, the orifice in electrode 166, multipole ion guide 155, the orifice in electrode 167, multipole ion guide 156, the orifice in electrode 168 to detector 165. The pressures in vacuum stages 151, 152 and 153 are typically maintained at 1 torr, 5 millitorr and <1×10−5 torr respectively while the pressure inside collision cell 157 is maintained at 5 to 8 millitorr. Triple quadrupoles are configured to perform MS or a single MS/MS sequence mass analysis function. In an MS/MS experiment, ions start at or near atmospheric pressure, are transported through multiple vacuum stages to a low pressure vacuum region where mass to charge selection occurs in multipole ion guide 154 with little or no ion to neutral collisions. Mass to charge selected ions are then are accelerated into a region of elevated pressure in collision cell multipole ion guide 155. The resulting fragment ion population are directed the low pressure region in quadrupole 156 where mass to charge separation is conducted with few or no ion to neutral collisions prior to detection by ion detector 165. A similar analytical ion sequence occurs in prior art hybrid quadrupole, quadrupole TOF mass analyzers where third quadrupole 156 is replaced by a TOF mass analyzer residing in a fourth vacuum pumping stage.
The placement of a multipole ion guide collision cell in a low pressure vacuum stage increases the cost and complexity of an API MS/MS mass analyzer. One aspect of the invention is the configuration of multiple quadrupole ion guides in a higher pressure vacuum pumping stage of an API source using the background pressure formed by the gas leak from atmospheric pressure to perform CID ion fragmentation. Mass to charge selection and CID ion fragmentation is performed in the second vacuum stage of an Atmospheric Pressure Ion Source mass analyzer, eliminating the need for a separate collision cell with its additional gas loading on the vacuum system. The configuration of multiple quadrupoles in the second vacuum stage reduces the system vacuum pumping speed requirements and its associated costs for API quadrupole and hybrid mass analyzers. Another aspect of the invention is the configuration of multiple quadrupole ion guides that have pole dimensions considerably reduced in size from quadrupole assemblies typically found in commercially available triple quadrupoles or hybrid quadrupole TOF mass analyzers. The smaller pole dimensions and reduced quadrupole length minimizes the ion transmission time along each quadrupole assembly axis. This increases the analytical speed of the mass spectrometer for a range of mass analysis functions. The reduced quadrupole size require less space and power to operate, decreasing system size and cost without decreasing performance. Another aspect of the invention is the configuration of a multipole ion guide that extends continuously into multiple vacuum stages into the multiple quadrupole assembly positioned in the higher pressure region of an API MS instrument. Multiple vacuum pumping stage ion guides are described in U.S. Pat. No. 5,652,427. As will be described below, configuring a multiple vacuum stage quadrupole ion guide with additional quadrupole ion guides enables operation over a wide range of mass analysis functional sequences.
Individual quadrupole ion guide assemblies require individual RF, +/− DC and supplemental resonant frequency voltage supplies to achieve ion mass to charge selection, CID ion fragmentation and trapping functions. Quadrupole ion guides have been configured with segments where common RF voltage from a single RF supply is applied to all segments of the ion guide assembly or rod set. Typically, an RF only entrance and exit segment will be configured in a quadrupole rod set to minimize fringing field effects on ions entering or leaving the quadrupole. The RF voltage is applied to the entrance and exit sections through capacitive coupling with the primary RF supplied to the central rod segment. Offset potentials, that is the common DC voltage applied to all four poles of a given segment, can be set individually on each segment to accelerate ions from one ion guide segment to the next within a quadrupole ion guide assembly. The offset potential applied to segments of an ion guide can be set to trap ions within an ion guide as well. In the prior art, electrodes are positioned between individual multipole ion guides when multiple ion guide assemblies are configured in a mass analyzer. Referring to the prior art triple quadrupole example diagramed in FIG. 20 each quadrupole ion guide is separated from an adjacent ion guide by an electrode. Electrodes are configured to minimize the fringing field effects as ions pass from one ion guide assembly to the next. They minimize any capacitive coupling between different ion guide sets avoiding beat frequency distortions of the RF fields. The electrodes also serve the additional purpose of providing a reduced orifice between vacuum pumping stages or between a collision cell and the vacuum stage in which it resides to minimize gas conductance. When conducting MS/MS experiments, i.e. the collision cell is maintained at a pressure of 5 to 8 millitorr, ions transferred from one quadrupole to another in the prior art must pass through a background pressure gradient. The collisional effects that occur in the fringing field region between multipole ion guides may cause ion losses due to scattering effects.
Referring to FIG. 20, multipole ion guide 158 is separated from quadrupole assembly 154 by vacuum partition and electrode 161. Quadrupole 154 is diagramed with RF only segments or sections 162 and 170 and analytical segment 163. Multipole ion guide 158 may be configured as a quadrupole, hexapole or octapole and may have a different RF voltage supply from that of quadrupole 154. The RF frequency, amplitude, phase and different RF related electric fields produced by a difference in the number of poles between ion guide 158 and quadrupole 154 create fringing fields that can negatively effect the efficiency of ion transport from ion guide 158 into quadrupole 154. The effect on ion trajectories of exit fringing fields of multipole ion guide 158 and the entrance fringing fields of quadrupole 154 are reduced by electrode 161 and RF only segments 162. Electrodes 166 and 167 serve the similar functions of reducing fringing field effects and acting as a vacuum partitions. Collision cell multipole ion guide may be configured with four, six or eight poles and have RF fields at its entrance and exit ends that differ from the RF and DC fields of the adjacent quadrupole ion guides. Ion losses occur at each transfer from one multipole ion guide assembly to the next due to ion collisional scattering, fringing field effects and ion collisions with the electrodes. One aspect of the invention is the configuration of multiple quadrupole assemblies along a common axis with no electrode partitions in between. Each quadrupole assembly configured according to the invention can individually conduct mass selection and CID fragmentation of ions. One or more multiple vacuum stage quadrupole can be configured, according to the invention in a multiple quadrupole assembly. Ijames, Proceedings of the 44th ASMS Conference on Mass Spectrometry and Allied Topics, 1996, p 795, proposes a linear combination of four quadrupole ion guides operated in RF only ion transport and trapping mode with ion pulsing into a TOF mass analyzer. Two of the quadrupoles in the proposed assembly extend continuously into two vacuum pumping stages. The extended abstract does not teach applying different RF potentials to quadrupoles one through four. Nor does it teach conducting mass to charge selection or CID fragmentation operation with the proposed multiple quadrupole assembly as is included as aspects of the present invention.
Separate RF voltage supplies providing RF voltage to individual multipole ion guide assemblies in the present invention can be operated with a common frequency and phase to minimize RF fringing field effects. Each quadrupole assembly can have different RF amplitude applied during mass to charge selection and/or ion CID fragmentation operation. Eliminating the electrodes between quadrupole ion guide assemblies increases ion transmission efficiency and allows ions to be directed forward and backward between quadrupole ion guide assemblies. Efficient bidirectional transport of ions along the axis of a multiple quadrupole assembly allows a wide range analytical functions to be run on a single instrument. A equivalent array of analytical functions would require more than one prior art mass analyzer to achieve. One aspect of the invention includes RF quadrupoles configured between each analytical quadrupole assembly to minimize any fringing fields due to interquadrupole differences in RF amplitude, +/− DC voltage and resonant frequency voltages. The RF only segments, configured with individual RF supplies, also serve to minimize RF or resonant frequency coupling between analytical quadrupole ion guide assemblies. In another aspect of the invention, the RF only quadrupoles may be configured as RF only segments of each quadrupole assembly capacitively coupling to the adjacent quadrupole ion guide RF supply. In yet another aspect of the invention, the junctions between individual quadrupole assemblies are located in the higher pressure vacuum region where little pressure gradient exists at the junction between quadrupole assemblies. Ion collisions with the background gas serve to damp stable ion trajectories to the quadrupole centerline where fringing field effects between quadrupoles are minimized. This collisional damping of ions trajectories by the background gas serves to maximize ion transmission in the forward and backward direction between individual quadrupole ion guide assemblies.
Triple quadrupoles, three dimensional ion traps, hybrid quadrupole-TOFs, hybrid magnetic sector and Fourier Transform (FTMS) mass analyzers can perform MS/MS analysis. Ion traps and FTMS mass analyzers can perform MS/MSn analysis, however, ion CID fragmentation is performed with relatively low energy resonant frequency excitation. CID fragmentation in triple quadrupoles and hybrid quadrupole-TOF mass analyzers is achieved by acceleration of ions along the quadrupole axis referred to herein as DC acceleration CID fragmentation. Ions are generally accelerated with a few to tens of eV in quadrupole DC acceleration CID fragmentation. Hybrid or tandem magnetic sector mass analyzers can perform high energy DC acceleration ion fragmentation with ions accelerated into gas phase collisions with hundreds or even thousands of eV. Single mass range mass to charge selection in triple quadrupoles is achieved by applying RF and +/− DC to the non collision cell quadrupole assemblies 154 and 156 in FIG. 21. Single or multiple range mass to charge selection in three dimensional ion traps is achieved using RF voltage amplitude scanning coupled with resonant frequency ejection of unwanted ions. Triple quadrupoles operate with a continuous ion beam delivered from an API source. Ion traps must analyze ions provide in a continuous ion beam in batch-wise manner. The space charge of trapped ions in a three dimensional ion trap imposes performance restrictions not encountered in triple quadrupole operation. The effects of space charge in an ion trap potentially limit its utility in quantitative analysis applications. The mass to charge selection resolution in quadrupole ion guides operated in low vacuum pressures is limited in part by the ion transit time. Each mass analyzer type performs ion mass to charge selection and CID fragmentation through a different means each with its own advantages and disadvantages depending on the analytical problem to be solved.
Quadrupoles and three dimensional ion trap mass analyzers and recently hybrid quadrupole-TOF mass analyzers have become the most widely used mass analyzer types interfaces with Atmospheric Pressure Ion Sources such as Electrospray (ES) and Atmospheric Pressure Chemical Ionization (APCI) sources. FTMS instruments provide very high resolution and mass accuracy but price and operational complexity have limited the number of units currently in use. It is one aspect of the present invention to combine the functional capabilities of triple quadrupoles, three dimensional ion traps and hybrid quadrupole-TOF mass analyzers into a single instrument. The invention includes but is not limited to resonant frequency CID ion fragmentation, DC acceleration CID fragmentation even for energies over one hundred eV, RF and +/− DC mass to charge selection, single or multiple mass range RF amplitude and resonant frequency ion ejection mass to charge selection, ion trapping in quadrupole ion guides and TOF mass analysis. The invention enables mass spectrometric analytical functions that can not be performed any prior art mass analyzer type. For example, MS/MSn where n>1 can be performed on a hybrid quadrupole-TOF's configured according to the invention, using DC acceleration fragmentation for each CID step or combinations of resonant frequency excitation and DC acceleration CID ion fragmentation. Ion trapping with mass to charge selection of CID ion fragmentation can be performed in each individual quadrupole assembly without stopping a continuous ion beam. These techniques, according to the invention, as described below increase the duty cycle and sensitivity of a hybrid quadrupole-TOF during MS/MS experiments.
The hybrid quadrupole-TOF configured according to the inventions is a lower cost bench-top instrument that includes all the performance capability as described in U.S. Pat. Nos. 5,652,427 and 5,689,111 and U.S. patent application Ser. Nos. 08/694,542 and 60/021,184 included herein by reference. Emulation and improved performance of prior art API triple quadrupole, three dimensional ion trap, TOF and hybrid quadrupole-TOF mass analyzer functions can be achieved with the hybrid quadrupole-TOF mass analyzer configured according to the invention. The assemblies of multiple quadrupole ion guides configured according to the invention can be interfaced to all mass analyzer types tandem an hybrid instruments and most ion source types that produce ions from gas, liquid or solid phases.